rs587779751

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003073.5(SMARCB1):c.897G>A(p.Ser299=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,008 control chromosomes in the GnomAD database, including 10,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 880 hom., cov: 33)

Exomes 𝑓: 0.11 ( 10101 hom. )

Consequence

SMARCB1
NM_003073.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -3.33

Variant links:

Genes affected

SMARCB1 (HGNC:11103): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

SMARCB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 22-23825326-G-A is Benign according to our data. Variant chr22-23825326-G-A is described in ClinVar as [Benign]. Clinvar id is 126368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23825326-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-3.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SMARCB1	NM_003073.5 linkuse as main transcript	c.897G>A	p.Ser299=	synonymous_variant	7/9	ENST00000644036.2	NP_003064.2
SMARCB1	NM_001362877.2 linkuse as main transcript	c.951G>A	p.Ser317=	synonymous_variant	7/9		NP_001349806.1
SMARCB1	NM_001317946.2 linkuse as main transcript	c.924G>A	p.Ser308=	synonymous_variant	7/9		NP_001304875.1
SMARCB1	NM_001007468.3 linkuse as main transcript	c.870G>A	p.Ser290=	synonymous_variant	7/9		NP_001007469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCB1	ENST00000644036.2 linkuse as main transcript	c.897G>A	p.Ser299=	synonymous_variant	7/9		NM_003073.5	ENSP00000494049	A1	Q12824-1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

16051

AN:

152170

Hom.:

880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0860

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.0884

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.0750

Gnomad SAS

AF:

0.170

Gnomad FIN

AF:

0.130

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.115

Gnomad OTH

AF:

0.112

GnomAD3 exomes

AF:

0.112

AC:

28247

AN:

251442

Hom.:

1764

AF XY:

0.116

AC XY:

15827

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.0866

Gnomad AMR exome

AF:

0.0770

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.0777

Gnomad SAS exome

AF:

0.176

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.114

GnomAD4 exome

AF:

0.114

AC:

166761

AN:

1461720

Hom.:

10101

Cov.:

AF XY:

0.116

AC XY:

84346

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.0854

Gnomad4 AMR exome

AF:

0.0787

Gnomad4 ASJ exome

AF:

0.107

Gnomad4 EAS exome

AF:

0.0460

Gnomad4 SAS exome

AF:

0.176

Gnomad4 FIN exome

AF:

0.128

Gnomad4 NFE exome

AF:

0.113

Gnomad4 OTH exome

AF:

0.117

GnomAD4 genome

AF:

0.105

AC:

16048

AN:

152288

Hom.:

880

Cov.:

AF XY:

0.106

AC XY:

7884

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0858

Gnomad4 AMR

AF:

0.0884

Gnomad4 ASJ

AF:

0.101

Gnomad4 EAS

AF:

0.0747

Gnomad4 SAS

AF:

0.169

Gnomad4 FIN

AF:

0.130

Gnomad4 NFE

AF:

0.115

Gnomad4 OTH

AF:

0.111

Alfa

AF:

0.101

Hom.:

592

Bravo

AF:

0.0997

Asia WGS

AF:

0.106

AC:

367

AN:

3478

EpiCase

AF:

0.114

EpiControl

AF:

0.115

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2016	Variant summary: The SMARCB1 c.897G>A (p.Ser299Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant along with 3/5 splice tools predicting the variant not to have an impact on normal splicing. This variant was found in 13842/121354 control chromosomes (893 homozygotes), predominantly observed in the South Asian (284 homozygotes) subpopulation at a frequency of 0.1737945 (2869/16508). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic SMARCB1 variant (0.0000001), suggesting this is a benign polymorphism found primarily in the populations of South Asian origin. One clinical diagnostic laboratory classified this variant as Benign. Taken together, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Rhabdoid tumor predisposition syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Schwannomatosis 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.13

DANN

Benign

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over